Method of treating pain with draflazine-analogues

ABSTRACT

This invention concerns the use of nucleoside transport inhibitors, more particularly compounds of formula                    
     an N-oxide form, a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof, wherein R 1  is C 1-4 alkyl, aminocarbonyl or mono- or di(C 1-4 alkyl)aminocarbonyl, Ar is a phenyl or pyridinyl derivative and L is a radical of formula                    
     wherein Ar 1  is a phenyl derivative; Ar 2  is a phenyl or pyridinyl derivative; and Alk is C 1-4 alkanediyl; for the manufacture of a medicine for the treatment of warm-blooded animals suffering from pain.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the national stage of application Ser. No.PCT/EP98/03664, filed on Jun. 9, 1998 which application claims priorityfrom EP No. 97201813.9, filed on Jun. 16, 1997.

The present invention is concerned with the use of nucleoside transportinhibitors, in particular compounds of formula (I) for the manufactureof a medicament for the treatment of warm-blooded animals, includinghumans, suffering from chronic pain conditions, such as neuropathicpain.

Nucleoside Transport Inhibition

Nucleoside transport inhibition is a pharmacological activity mainlyassociated with treatment of problems arising during myocardial ischemiaand reperfusion. Indeed adenosine exhibits a multitude ofpharmacological properties which makes it particularly suitable fortackling the above mentioned problems. The nucleoside transporter playsa key role in the catabolism and fate of endogenous adenosine, producedin the interstitial space during ischemia. Being located almostexclusively in endothelial cells lining the vasculature, thistransporter facilitates diffusion according to the existing gradient.Hence, because of extensive catabolism within these cells, thetransporter accelerates adenosine breakdown. In addition, if perfusionprevails or during reperfusion, when the vascular compartmentconstitutes a major sink, the transporter will carry the adenosine,surviving intra-endothelial metabolism, into the lumen and enhance thewashout. Paracellular passage (via clefts in between the endotheliallayer) seems to be a very slow process, so that the main escape ofadenosine (and inosine) through the endothelial barrier depends on afunctioning transporter. While not provoking adenosine formation,inhibition of the transporter will considerably prolong the presence ofadenosine at its site of formation by preventing uptake and catabolismin the endothelial cells.

An overview of how nucleoside transport inhibition can be experimentallydetermined is given in “Comparative pharmacology of nucleoside transportinhibitors” in Nucleosides and Nucleotides 10:975-982, 1991 (Van BelleH, Janssen P A J).

Known potent nucleoside transport inhibitors are dipyridamole, dilazep,and members of lidoflazine family (e.g. lidoflazine, mioflazine,soluflazine, R 75231 and draflazine, which is the (−)-enantiomer of R75231).

The only nucleoside transport inhibitor thus far approved for humantherapy is dipyridamole. The mean therapeutic uses for dipyridamole arethe prophylaxis of angina pectoris and as an antithrombotic.

Other nucleoside transport inhibitors are the compounds of formula (I)as shown hereinafter.

Some compounds of formula (I) are disclosed in the prior art asinhibitors of nucleoside transport through membranes, in particular3-(aminocarbonyl)-4-[4,4-bis(4-fluoro-phenyl)-butyl]-N-(2,6-dichlorophenyl)-1-piperazineacetamidedihydrochloride monohydrate, generically known as mioflazine, isdescribed in Molecular Physiology 8:615-630 (1985). In EP-A-0,068,544,published on Jan. 5, 1983, and WO-91/07967, published on Jun. 13, 1991,N-aryl-piperazinealkanamides, in particularS-(−)-2-(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl)-4-[5,5-bis(4-fluorophenyl)-pentyl]-1-piperazineacetamide,generically known as draflazine, are disclosed as agents useful forprotecting the heart from myocardial injury caused by ischaemia orhypoxia. EP-A-0,285,219, published on Oct. 5, 1988, disclosesN-aryl-piperazine-alkanamides for improving sleep or counteracting sleepdisorders.

In the European Journal of Pharmacology, vol 11, no 1, Jul. 1, (1970)Türker et al. disclose lidoflazine significantly increased reaction timeof mice to thermal stimulation and increased pain treshold to electricalstimulation of incisor teeth in rabbits, but not of canine teeth indogs. The pain stimuli used in these models are typically acute painstimuli. These types of pain are not related to chronic pain conditions,more particularly neuropatic pain.

In the Eur. J. Pharmacol., Mol. Pharmacol. Sect.,1989, 273-81, Ijzermanet al introduce a new series of compounds related to the nucleosidetransport inhibitors, lidoflazine and mioflazine. The article does notmention any relationship between these compounds and pain, morespecifically chronic pain conditions, more particularly neuropathicpain.

In the European Journal of Clinical Pharmacology, 51(1) (1996) 7-13Andersen et al discuss a randomized, double-blind, placebo-controlledstudy, wherein the tolerability and safety of draflazine in thetreatment of patients with unstable angina was evaluated. The articlediscloses that the mean duration of chest pain during the 24 hourobservation period was 91.4 min in the placebo group (i.e. the group nottreated with draflazine) compared to 75.5 min in draflazine treatedpatients. The chest pain experienced by these patients is not a chronicpain condition, more particularly neuropathic pain.

Surprisingly it has now been found that the compounds of formula (I) areuseful for the treatment of warm-blooded animals suffering from chronicpain conditions such as neuropatic pain, inflammatory pain and cancerpain.

The present invention concerns the use of nucleoside transportinhibitors, and especially the compounds of formula

the N-oxide forms, the pharmaceutically acceptable acid addition saltsand the stereochemically isomeric forms thereof, wherein

R¹ is C₁₋₄alkyl, aminocarbonyl or mono- or di(C₁₋₄alkyl)aminocarbonyl;

L is a radical of formula

wherein

Ar¹ is phenyl, phenyl substituted with halo or C₁₋₄alkyloxy;

Ar^(2 y)is phenyl; phenyl substituted with halo, C₁₋₄alkyloxy; orpyridinyl;

Alk is C₁₋₄alkanediyl;

Ar is a radical of formula

wherein

R² and R³ each independently are halo or C₁₋₄alkyl;

R⁴ is hydrogen, halo, nitro, amino, mono- or di(C₁₋₄alkyl)amino,C₁₋₄alkylcarbonylamino, aminocarbonylamino, C₁₋₄alkyl, C₁₋₄alkyloxy,C₁₋₄alkyloxycarbonyl, C₁₋₄alkylcarbonyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, cyano or aminomethyl;

R⁵ is C₁₋₄alkylcarbonyl;

R⁶ is hydrogen, amino, mono- or di(C₁₋₄alkyl)amino,C₁₋₄alkylcarbonylamino, aminocarbonylamino, aminocarbonyl or cyano;

R⁷ is C₁₋₄alkyl;

R⁸ is halo or C₁₋₄alkylcarbonyl;

R⁹ is hydrogen or C₁₋₄alkyl;

R¹⁰ is halo or C₁₋₄alkyl;

R¹¹ is hydrogen, hydroxy or C₁₋₄alkyl;

R¹² is halo or C₁₋₄alkyl;

R¹³ is hydrogen or;

R¹² and R¹³ taken together may also form a C₃₋₅alkanediyl radical;

each R¹⁴ is C₁₋₄alkyl; and

R¹⁵ is C₁₋₄alkyl or amino;

for the manufacture of a medicine for the treatment of warm-bloodedanimals suffering from pain.

As used in the foregoing definitions and hereinafter, halo is generic tofluoro, chloro, bromo and iodo; C₁₋₄alkyl defines straight and branchedchain saturated hydrocarbon radicals having from 1 to 4 carbon atomssuch as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl,2-methylpropyl, 2,2-dimethylethyl and the like; C₁₋₄alkanediyl definesbivalent straight and branched chain saturated hydrocarbon radicalshaving from 1 to 4 carbon atoms such as, for example, methylene,1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the like;C₃₋₅alkanediyl defines bivalent straight and branched chain saturatedhydrocarbon radicals having from 3 to 5 carbon atoms such as, forexample, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl and the like.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of formula (I) are able toform. The compounds of formula (I) which appear in their free form as abase can be converted in their acid addition salt by treating said freebase form with an appropriate acid. Appropriate acids comprise, forexample, inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid; sulfuric; nitric; phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid),maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) as well as the salts thereof, areable to form. Such solvates are for example hydrates, alcoholates andthe like.

Some compounds of the present invention may exist in differenttautomeric forms and all such tautomeric forms are intended to beincluded within the scope of the present invention. For instance,compounds of formula (I) wherein Ar is a radical of formula (b-4), i.e.a pyridinyl, substituted with hydroxy, may exist in their correspondingtautomeric form.

The term stereochemically isomeric forms as used hereinbefore definesthe possible different isomeric as well as conformational forms whichthe compounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of compounds denotes the mixture, inparticular the racemic mixture, of all possible stereochemically andconformationally isomeric forms, said mixtures containing alldiastereomers, enantiomers and/or conformers of the basic molecularstructure. All stereochemically isomeric forms of the compounds offormula (I) both in pure form or in admixture with each other areintended to be embraced within the scope of the present invention.

The N-oxide forms of the compounds of formula (I) are meant to comprisethose compounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide, particularly those N-oxides whereinthe piperazine-nitrogen is N-oxidized.

A particular group of compounds of formula (I) are those wherein

R¹ is aminocarbonyl or (C₁₋₄alkyl)aminocarbonyl;

L is a radical of formula (a-1) or (a-2) wherein

Ar¹ is phenyl or phenyl substituted with halo;

Ar² is phenyl, phenyl substituted with halo, or pyridinyl;

Alk is C₁₋₄alkanediyl;

Ar is a radical of formula b-1) or (b-3) wherein

R² and R³ each independently are halo or C₁₋₄alkyl;

R⁴ is hydrogen, C₁₋₄alkyl, halo, nitro, amino, cyano or aminocarbonyl;

R⁷ is C₁₋₄alkyl;

R⁸ is halo or C₁₋₄alkylcarbonyl; and

R⁹ is hydrogen or C₁₋₄alkyl.

A more particular group of compounds are those particular compoundswherein

R¹ is aminocarbonyl or methylaminocarbonyl;

L is a radical of formula (a-1) or (a-2) wherein

Ar¹ is phenyl or phenyl substituted with fluoro, in particular 4-fluoro;

Ar² is phenyl, phenyl substituted with fluoro, in particular 4-fluoro,or pyridinyl;

Alk is C₃₋₄alkanediyl;

Ar is a radical of formula (b-1) or (b-3) wherein

R² and R³ each independently are chloro or methyl;

R⁴ is hydrogen, methyl, chloro, amino, cyano or aminocarbonyl;

R⁷ is methyl;

R⁸ is chloro or methylcarbonyl; and

R⁹ is hydrogen.

Most preferred compounds of formula (I) are

2-(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl)-4-[5,5-bis(4-fluorophenyl)-pentyl]-1-piperazineacetamide;and

S-(−)-2-(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl)-4-[5,5-bis(4-fluorophenyl)-pentyl]-1-piperazineacetamide;the stereoisomeric forms, the pharmaceutically acceptable acid additionsalts and the N-oxide forms thereof.

Novel compounds of formula (I) are3-(aminocarbonyl)-N-(2,6-dichloro-phenyl)-4-[4-(4-fluorophenyl)-4-(3-pyridinyl)-butyl]-1-piperazineacetamide,andN-(2-acetyl-6-chlorophenyl)-4-[5,5-bis(4-fluorophenyl)-4-pentenyl]-3-[(methyl-amino)carbonyl]-1-piperazineacetamide.

The compounds of formula (I) can be prepared as described inEP-0,068,544, EP-A-0,285,219, U.S. Pat. Nos. 4,968,684, 5,026,853 andEP-A-0,455,789. In general, they can be prepared by N-alkylating anintermediate of formula (II) with an intermediate of formula (III), orby N-alkylating an intermediate of formula (IV) with an intermediate offormula (V).

In the above reaction scheme, W is an appropriate leaving group such as,for example, chloro, bromo, methanesulfonyloxy or benzenesulfonyloxy.The reaction can be performed in a reaction-inert solvent such as, forexample, toluene, dichloromethane, methyl isobutylketone,N,N-dimethylacetamide or N,N-dimethylformamide, in the presence of asuitable base such as, for example, sodium carbonate, sodium hydrogencarbonate or triethylamine, and optionally in the presence of potassiumiodide. Stirring may enhance the rate of the reaction. The reaction mayconveniently be carried out at a temperature ranging between roomtemperature and reflux temperature of the reaction mixture.

The compounds of formula (I) can also be converted into each otherfollowing art-known procedures of functional group transformations.

The preparation of intermediates of formula (II), (III), (IV) and (V) isdescribed in EP-0,068,544, EP-A-0,285,219, U.S. Pat. Nos. 4,968,684 and5,026,853.

Compounds of formula (I) and some of the intermediates in the presentinvention contain at least one asymmetric carbon atom in theirstructure, namely the piperazine carbon atom bearing the R¹-radicalwhich may be present in a R- or S-configuration. Consequently, thecompounds of formula (I) may be present in two different enantiomericforms, which may be separated from each other. Pure stereochemicallyisomeric forms of said compounds and said intermediates can be obtainedby the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. An alternative manner of separating the enantiomeric formsof the compounds of formula (I) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

Pure stereochemically isomeric forms of the compounds of formula (I) mayalso be obtained from the pure stereochemically isomeric forms of theappropriate intermediates and starting materials, provided that theintervening reactions occur stereospecifically. The pure and mixed, inparticular racemic, stereochemically isomeric forms of the compounds offormula (I) are intended to be embraced within the scope of the presentinvention.

The pain-relieving properties of the compounds of formula (I) areillustrated by the “Formalin test on guinea pigs”, described in ExampleB.1, which demonstrates the acute and chronic pain-relieving effect ofthe subject compounds.

In view of their favourable pain-relieving properties, the compounds offormula (I), the pharmaceutically acceptable addition salts,stereochemically isomeric forms and N-oxide forms thereof, are useful totreat or relieve warm-blooded animals suffering from chronic painconditions, such as neuropathic pain, inflammatory pain, cancer pain.These conditions are related to hyperalgesia and allodynia. Theseconditions might include acute pain, skeletal muscle pain, low backpain, upper extremity pain, fibromyalgia and myofascial pain syndromes,orofacial pain, abdominal pain, phantom pain, tic douloureux andatypical face pain, nerve root damage and arachnoiditis, geriatric pain,central pain, inflammatory pain.

In particular, the subject compounds are useful to treat chronicnon-cancer pain such as, neuropathic pain. Neuropathic pain results fromlesions in the peripheral or central nervous system. It is oftenassociated with somatosensory deficits and the distribution of pain ismostly related to the area of somatosensory dysfunction. The onset ofthe pain can be delayed after the causative event, even up to months oryears. There are several causes of neuropathic pain with a considerablevariability in symptoms and neurological deficits. Examples areperipheral nerve damage due to traumatic injury compression, ischemia,toxins, nutritional deficiencies, infections and complications of liverand kidney.

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes. To prepare the pharmaceutical compositions ofthis invention, an effective amount of a particular compound, in base oracid addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for administration orally, rectally, percutaneously, or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols and the like in the case oforal liquid preparations such as suspensions, syrups, elixirs andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, to aid solubility for example, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. In the compositions suitable for percutaneous administration,the carrier optionally comprises a penetration enhancing agent and/or asuitable wetting agent, optionally combined with suitable additives ofany nature in minor proportions, which additives do not cause asignificant deleterious effect to the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. It is especially advantageous to formulate theaforementioned pharmaceutical compositions in dosage unit form for easeof administration and uniformity of dosage. Dosage unit form as used inthe specification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

Those skilled in the art could easily determine the effective amountfrom the test results presented hereinafter. In general it iscontemplated that an effective amount of a compound of formula (I) wouldbe from 0.001 mg/kg to 100 mg/kg body weight, and in particular from0.01 mg/kg to 10 mg/kg body weight. It may be appropriate to administerthe required dose as two, three, four or more sub-doses at appropriateintervals throughout the day. Said sub-doses may be formulated as unitdosage forms, for example, containing 0.1 to 500 mg, and in particular 1mg to 200 mg of compound of formula (I) per unit dosage form. Inparticular, said sub-doses are formulated as an oral dosage form beingeither a solid such as, e.g. tablets (both swallowable-only and chewableforms), capsules, gelcabs and the like, or a liquid.

The compounds of formula (I), the pharmaceutically acceptable additionsalts, stereochemically isomeric forms and N-oxide forms thereof, mayconveniently be used in combination with an analgesic such as, forexample, nonnarcotic analgesics, e.g. aspirin or acetaminophen; NSAIDS(nonsteroidal antiinflammatory drugs), e.g. ibuprofen, naproxen,fenoprofen, ketoprofen, flurbiprofen, fenbufen, indomethacin and thelike; opioids, e.g. codeine, morphine, naloxone, buprenorphine,pentazocine, fentanyl and the like; antidepressants, e.g. doxepin,fluoxetine, paroxetine and the like; ion channel modulators and/ormembrane stabilising agents, e.g. lidocaine or mexiletine; α2-adrenergicagonists, e.g. clonidine; capsaicin analogues; or NMDA(N-methyl-D-aspartate) receptor antagonists, e.g. ketamine. Theinvention thus provides a combination comprising a composition asdefined herein, together with an analgesic. The combination may beadministered separately, simultaneously, concurrently or consecutivelyby any of the routes described above, or the combination may also bepresented in the form of one pharmaceutical formulation. Thus, apharmaceutical product comprising (a) a compound of formula (I) and (b)an analgesic as defined hereinbefore, as a combined preparation forsimultaneous, separate or sequential use in the treatment ofwarm-blooded animals suffering from pain. Such a product may comprise akit comprising a container containing a pharmaceutical composition of acompound of formula (I), and another container comprising apharmaceutical composition of the analgesic. The product with separatecompositions of the two active ingredients has the advantage thatappropriate amounts of each component, and timing and sequence ofadministration can be selected in function of the patient.

When compounds of formula (I) are used in combination with an analgesic,the dose of the analgesic may vary from the dose when used alone. Thuswhen compounds of formula (I) are used together with an analgesic thedose of the latter may be the same or more commonly, lower, than thedose employed when the analgesic is used alone. Appropriate doses willbe readily appreciated by those skilled in the art.

In view of the above uses of the compounds of formula (I), it followsthat the present invention also provides a method of treatingwarm-blooded animals suffering from pain, said method comprising theoral or systemic administration of a therapeutic amount of a compound offormula (I) effective in relieving pain.

The following examples are intended to illustrate and not to limit thescope of the present invention.

EXPERIMENTAL PART

Hereinafter “THF” means tetrahydrofuran, “DCM” means dichloromethane,“DIPE” means diisopropylether, “DMF” means N,N-dimethylformamide and“MIK” means methyl isobutyl ketone.

A. Preparation of the Final Compounds Example A.1

A mixture of 6.7 g of 1,1′-(4-iodobutylidene)bis[4-fluorobenzene], 5.2 gof3-[(methylamino)carbonyl]-N-(2,4,6-trimethylphenyl)-1-piperazineacetamide,2.3 g sodium carbonate and 38 ml DMF is stirred for 18 hours at 70° C.The reaction mixture is cooled and poured onto ice-water. The product isextracted with DCM. The extract is washed with water, dried, filteredand evaporated. The residue is purified by column-chromatography oversilica gel using a mixture of trichloromethane and methanol (95:5 byvolume) as eluent. The pure fractions are collected and the eluent isevaporated. The residue is dried, yielding 4.23 g of4-[4,4-bis(4-fluorophenyl)butyl]-3-[(methylamino)-carbonyl]-N-(2,4,6-trimethylphenyl)-1-piperazineacetamide(compound 1, mp. 82.3° C.).

Example A.2

A mixture of 5.8 g of4-[4,4-bis(4-fluorophenyl)butyl]-N-methyl-2-piperazine-carboxamide, 3.6g of 2-chloro-N-(2,4,6-trimethylphenyl)acetamide, 2.12 g of sodiumcarbonate and 150 ml of MIK is stirred and refluxed for 18 hours. Thereaction mixture is cooled and washed with water. The organic phase isdried, filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue isdried, yielding 4.34 g of4-[4,4-bis(4-fluorophenyl)butyl]-2-[(methylamino)carbonyl]-N-(2,4,6-trimethylphenyl)-1-piperazineacetamide(compound 2, mp. 90.2° C.).

Example A.3

A mixture of1-[4-(4-fluorophenyl)-4-(3-pyridinyl)butyl]-2-piperazinecarboxamide(6.75 g), 2-chloro-N-(2,6-dichlorophenyl)acetamide (5.24 g), sodiumcarbonate (3.16 g) and DMF (143 ml) was stirred for 4 hours at 70° C.The reaction mixture was evaporated and water was added to the residue.After extraction with DCM, the combined organic layers were washed withwater, dried, filtered and evaporated. The residue was purified bycolumn chromatography over silica gel (eluent:CHCl₃/CH₃OH 95/5). Thedesired fractions were collected and the solvent was evaporated. Theresidue was dissolved in 2-propanol and DIPE and converted into thehydrochloride salt. The salt was filtered off and dried, yielding 2.23 gof3-(amino-carbonyl)-N-(2,6-dichloro-phenyl)-4-[4-(4-fluorophenyl)-4-(3-pyridinyl)-butyl]-1-piperazineacetamidedihydrochloride.monohydrate (compound 14, mp. 226.3° C.).

Example A.4

A mixture of(±)-1-[5,5-bis(4-fluorophenyl)-4-pentenyl]-N-methyl-2-piperazine-carboxamide(4 g), N-(2-acetyl-6-chlorophenyl)-2-chloroacetamide (3.2 g) andtriethyl amine (75 ml) in DMF (75 ml) was stirred for 3 hours at 70° C.The solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent:CH₂Cl₂/CH₃OH 97/3). The desiredfractions were collected and the solvent was evaporated. The residue wasdissolved in 2-propanol and converted into the ethanedioic acid salt(1:2). The salt was filtered off and dried (vacuum; 70° C.), yielding3.72 g of(±)-N-(2-acetyl-6-chlorophenyl)-4-[5,5-bis(4-fluorophenyl)-4-pentenyl]-3-[(methylamino)carbonyl]-1-piperazineacetamideethanedioate (1:2) (compound 18, mp. 140° C.).

Tables 1 to 3 list the compounds that were prepared according to one ofthe above Examples.

TABLE 1

Co. Ex. Physical No No. R^(a) R^(b) n R¹ Ar data 1 1 F F 3 3-CONHCH₃2,4,6-tri- mp. methyl- 82.3° C. phenyl 2 2 F F 3 2-CONHCH₃ 2,4,6-tri-mp. methyl- 90.2° C. phenyl 3 2 F F 3 3-CONHCH₃ 5-chloro- .2HCl;2-methyl- mp. phenyl 190-225° C. 4 2 F F 3 2-CONHCH₃ 5-chloro- mp.2-methyl- 146.3° C. phenyl 5 2 F F 4 2-CONH₂ 2,6-dichloro- .2HCl; phenylmp. 178.1° C. 6 2 H H 4 2-CONH₂ 2,6-dichloro- mp. phenyl 149.6° C. 7 1 FF 4 3-CONH₂ 2,6-dichloro- .2HCl.H₂O; phenyl mp. 206.2° C. 8 2 F F 42-CONH₂ 2,6-trichloro- mp. phenyl 117.2° C. 9 1 F F 4 3-CONH₂2,6-dichloro- .2HCl.H₂O; 4-cyano- mp. phenyl 192.7° C. 10 1 F F 43-CONH₂ 4-amino- mp. carbonyl- 123.7° C. 2,6-dichloro- phenyl 11 1 F F 42-CONH₂ 4-amino- — 2,6-dichloro- phenyl 12 1 F F 4 2-CONH₂ 4-amino-R-(+)-; 2,6-dichloro- mp. phenyl 119.1° C. 13 1 F F 4 2-CONH₂ 4-amino-S-(−)-; 2,6-dichloro- mp. phenyl 124.1° C.

TABLE 2

Co. Ex. Physical data No No. n R¹ Ar (mp. in ° C.) 14 3 3 3-CONH₂2,6-dichlorophenyl .2HCl.H₂O; mp. 226.3° C. 15 1 4 3-CONH₂4-aminocarbonyl- .3HCl.2H₂O; 2,6-dichlorophenyl mp. 173.0° C.

TABLE 3

Co. Ex. Physical data No No. R^(a) R^(b) n R¹ Ar (mp. in ° C.) 16 1 F F3 3-CONHCH₃ 2,6-dichloro- mp. phenyl 101.5° C. 17 1 F F 4 2-CONH₂2,4,6-tri- mp. methyl- 127.2° C. phenyl 18 4 F F 3 3-CONHCH₃ 2-acetyl-.2(ethane- 6-chloro- dioate); phenyl mp. 140° C.

B. Pharmacological Example Example B.1

The pain-relieving potential of the compounds of formula (I) was assesedusing the “formalin test” on guinea pigs. Female guinea pigs (280-320 g)were starved overnight, weighed and placed in an observation cage. Onehour after intraperitoneal injection of a compound of formula (I),, a 5%formalin solution (0.05 ml) was injected in the right hindpaw of theguinea pig. During 5 minutes the flinching and licking responses werecounted. Over the next 25% minutes, the eyereflex and effect on muscletone was recorded. The left hindpaw of the guinea pig was also injectedwith 0.05 ml of a 5% solution of formalin and the same observations wererecorded. Afterwards, the animals were sacrificed. The estimatedeffective lowest dose of the compounds 1 to 18, whereby the number ofpain-induced responses was reduced by more than 50%, ranged between 0.63and 40 mg/kg body weight.

What is claimed is:
 1. A method of treating warm-blooded animalssuffering from chronic pain conditions comprising administering to saidanimals an effective amount of a nucleoside transport inhibitor.
 2. Themethod according to claim 1 wherein the nucleoside transport inhibitoris a compound of formula (I)

an N-oxide form, a pharmaceutically acceptable acid addition salt or astereochemically isomeric form thereof, wherein R¹ is C₁₋₄alkyl,aminocarbonyl or mono- or di(C₁₋₄alkyl)aminocarbonyl; L is a radical offormula

wherein Ar¹ is phenyl, phenyl substituted with halo or C₁₋₄alkyloxy; Ar²is phenyl; phenyl substituted with halo, C₁₋₄alkyloxy; or pyridinyl; Alkis C₁₋₄alkanediyl; Ar is a radical of formula

wherein R² and R³ each independently are halo or C₁₋₄alkyl; R⁴ ishydrogen, halo, nitro, amino, mono- or di(C₁₋₄alkyl)amino,C₁₋₄alkylcarbonylamino, aminocarbonylamino, C₁₋₄alkyl, C₁₋₄alkyloxy,C₁₋₄alkyloxycarbonyl, C₁₋₄alkylcarbonyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, cyano or aminomethyl; R⁵ isC₁₋₄alkylcarbonyl; R⁶ is hydrogen, amino, mono- or di(C₁₋₄alkyl)amino,C₁₋₄alkylcarbonylamino, aminocarbonylamino, aminocarbonyl or cyano; R⁷is C₁₋₄alkyl; R⁸ is halo or C₁₋₄alkylcarbonyl; R⁹ is hydrogen orC₁₋₄alkyl; R¹⁰ is halo or C₁₋₄alkyl; R¹¹ is hydrogen, hydroxy orC₁₋₄alkyl; R¹² is halo or C₁₋₄alkyl; R¹³ is hydrogen or; R¹² and R¹³taken together may also form a C₃₋₅alkanediyl radical; each R¹⁴ isC₁₋₄alkyl; and R¹⁵ is C₁₋₄alkyl or amino.
 3. The method according toclaim 2 wherein R¹ is aminocarbonyl or (C₁₋₄alkyl)aminocarbonyl; L is aradical of formula (a-1) or (a-2) wherein Ar¹ is phenyl or phenylsubstituted with halo; Ar² is phenyl, phenyl substituted with halo, orpyridinyl; Alk is C₁₋₄alkanediyl; Ar is a radical of formula (b-1) or(b-3) wherein R² and R³ each independently are halo or C₁₋₄alkyl; R⁴ ishydrogen, C₁₋₄alkyl, halo, nitro, amino, cyano or aminocarbonyl; R⁷ isC₁₋₄alkyl; R⁸ is halo or C₁₋₄alkyl-carbonyl; and R⁹ is hydrogen orC₁₋₄alkyl.
 4. The method according to claim 2 wherein R¹ isaminocarbonyl or methylaminocarbonyl; L is a radical of formula (a-1) or(a-2) wherein Ar¹ is phenyl or phenyl substituted with fluoro; Ar² isphenyl, phenyl substituted with fluoro, or pyridinyl; Alk isC₃₋₄alkanediyl; Ar is a radical of formula (b-1) or (b-3) wherein R² andR³ each independently are chloro or methyl; R⁴ is hydrogen, methyl,chloro, amino, cyano or aminocarbonyl; R⁷ is methyl; R⁸ is chloro ormethylcarbonyl; and R⁹ is hydrogen.
 5. The method according to claim 2wherein the compound is2-(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl)-4-[5,5-bis(4-fluorophenyl)-pentyl]-1-piperazineacetamide;orS-(−)-2-(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl)-4-[5,5-bis(4-fluorophenyl)-pentyl]-1-piperazineacetamide;the stereochemically isomeric forms, pharmaceutically acceptable acidaddition salts and the N-oxide forms thereof.
 6. The method according toclaim 1 wherein the chronic pain condition is neuropathic pain.
 7. Aproduct containing a) a composition comprising a therapeuticallyeffective amount of a compound according to claim 2 and apharmaceutically acceptable carrier; and b) a composition comprising atherapeutically effective amount of an analgesic and a pharmaceuticallyacceptable carrier, as a combined preparation for simultaneous, separateor sequential use in the treatment of pain.
 8. A compound of formula(I),

wherein the compound isN-(2-acetyl-6-chlorophenyl)-4-[5,5-bis(4-fluorophenyl)-4-pentenyl]-3-[(methyl-amino)carbonyl]-1-piperazineacetamide;the stereochemically isomeric forms, pharmaceutically acceptable acidaddition salts and the N-oxide forms thereof.
 9. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundas claimed in claim 8 and a pharmaceutically acceptable carrier.
 10. Themethod according to claim 3 wherein R¹ is aminocarbonyl ormethylaminocarbonyl; L is a radical of formula (a-1) or (a-2) whereinAr¹ is phenyl or phenyl substituted with fluoro; Ar² is phenyl, phenylsubstituted with fluoro, or pyridinyl; Alk is C₃₋₄alkanediyl; Ar is aradical of formula (b-1) or (b-3) wherein R² and R³ each independentlyare chloro or methyl; R⁴ is hydrogen, methyl, chloro, amino, cyano oraminocarbonyl; R⁷ is methyl; R⁸ is chloro or methylcarbonyl; and R⁹ ishydrogen.